Jun 11, 2013 - survival, greater bacterial burdens, and more cell death in the lungs. ... S4 was cultured on chocolate agar plates (prepared as previously ...
The American Journal of Pathology, Vol. 183, No. 4, October 2013
ajp.amjpathol.org
IMMUNOPATHOLOGY AND INFECTIOUS DISEASES
MyD88-Dependent Signaling Prolongs Survival and Reduces Bacterial Burden during Pulmonary Infection with Virulent Francisella tularensis Brian C. Russo,* Matthew J. Brown,* and Gerard J. Nau*yz From the Department of Microbiology and Molecular Genetics,* the Division of Infectious Diseases,y Department of Medicine, and the Center for Vaccine Research,z University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Accepted for publication June 11, 2013. Address correspondence to Gerard J. Nau, M.D., Ph.D., Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, W1157 BSTWR, 200 Lothrop St, Pittsburgh, PA 15261. E-mail: gjnau@pitt. edu.
Francisella tularensis is the causative agent of the debilitating febrile illness tularemia. The severe morbidity associated with F. tularensis infections is attributed to its ability to evade the host immune response. Innate immune activation is undetectable until more than 48 hours after infection. The ensuing inflammatory response is considered pathological, eliciting a septic-like state characterized by hypercytokinemia and cell death. To investigate potential pathological consequences of the innate immune response, mice deficient in a key innate immune signaling molecule, MyD88, were studied. MyD88 knockout (KO) mice were infected with the prototypical virulent F. tularensis strain, Schu S4. MyD88 KO mice succumbed to infection more rapidly than wild-type mice. The enhanced pathogenicity of Schu S4 in MyD88 KO mice was associated with greater bacterial burdens in lungs and distal organs, and the absence of IFN-g in the lungs, spleens, and sera. Cellular infiltrates were not observed on histological evaluation of the lungs, livers, or spleens of MyD88 KO mice, the first KO mouse described with this phenotype to our knowledge. Despite the absence of cellular infiltration, there was more cell death in the lungs of MyD88 KO mice. Thus, the host proinflammatory response is beneficial, and MyD88 signaling is required to limit bacterial burden and prolong survival during pulmonary infection by virulent F. tularensis. (Am J Pathol 2013, 183: 1223e1232; http://dx.doi.org/10.1016/j.ajpath.2013.06.013)
Inhalation of Francisella tularensis results in pneumonic tularemia, which is the most severe form of disease and associated with mortality rates up to 30% to 60% among untreated individuals.1,2 Additionally, its low infectious dose of
